Statistical Review and Evaluation
`
`Review of Carcinogenicity Data
`
`NDA#:
`
`Applicant:
`
`Drug Name:
`Indication:
`
`21 —344, #000
`
`AstraZeneca Pharmaceuticals LP
`
`Faslodex® (fulvestrant, ICl 182,780)
`~"‘""
`_.
`
`Document Reviewed:
`
`Electronic submissions dated October 29 and December 1 l, 200].
`
`Pharmacologist:
`
`Lilliam Rosario, PhD. (HFD-lSO)
`
`Statistical Reviewer:
`
`Peiling Yang, PhD. (HFD-710)
`
`Project Manager:
`
`Amy Baird. (HFD-150)
`
`Peiling Yang, PhD.
`Mathematical Statistician
`
`d”
`.—
`
`' m
`Concur:
`
`Ms. R Kelly
`Pre-clinical Coordinator, DBI
`
`.—
`
`g i 2
`Dr. G. Chi
`Division Director, DB?“
`
`CC:
`
`NDA# 21,344
`HFD-l SO/Amy Baird, CSO
`HFD—lSO/Division File
`HFD-l SO/Dr. L. Rosario
`HFD-lSO/Dr. D. Morse
`HFD-700/Dr. C. Anello
`
`HFD-710/Ms. R. Kelly
`HFD-71 O/Dr. G. Chen
`
`HFD-710/Dr. K. Mahjoob
`HFD-7lO/Dr. G. Chi
`
`HFD-7lO/Dr. P. Yang
`HFD-7l O/Chron
`
`

`

`TABLE OF CONTENTS
`
`]
`
`2
`
`3
`
`4
`
`BACKGROUND .................................................................................................................................. l
`
`INTRODUCTION ............................................................................................................................. l
`
`SUMMARY OF SPONSOR’S ANALYSIS ...................................................................................... 2
`
`REVIEWER’S ANALYSIS AND CONCLUSIONS ......................................................................... 2
`
`4.] REVIEWER'S ANALYSIS ...................................................................................................................... 2
`
`Comparisons among the Three Controls .................................................................................. 2
`4.1. 1
`Comparisons among Vehicle Controls and Treated, Excluding Saline Control ....................... 5
`4.1.2
`Comparisons among Vehicle Controls and Treated, Excluding Saline Control and High Dose
`4.1.3
`Level, Male Rats Only ............................................................................................................................ 8
`4.2 REVIEWER’S CONCLUSIONS ............................................................................................................... 9
`
`Conclusions for Comparisons among the Three Controls ........................................................ 9
`4.2.]
`Conclusions for Comparisons among the Two Vehicle Controls and the Treated.................... 9
`4.2.2
`42.3 Overall Conclusions .................................................................................................................. 9
`
`5
`
`APPENDIX ........................................................................................................................................ 10
`
`
`TUMOR FINDINGS FOR VEHICLE AND TREATED GROUPS, EXCLUDING SALINE CONTROL ................ 10
`5.1
`5.2 TUMOR FINDINGS FOR VEHICLE AND TREATED GROUPS, EXCLUDING SALINE CONTROL AND HIGH
`DOSE LEVEL, MALE RATS ONLY .............................................................................................................. 14
`
`TABLE OF TABLES
`
`Table I: Study Design ..........................................................................................................
`Table 2: Number of Deaths Per Control Group in Different Time Intervals. .....
`
`
`
`
`Table 4: Number of Deaths Per Treatment Group in Different Time Intervals, Excluding Saline ................. 6
`Table 5: Dose-Mortality Trend Tests, Excluding Saline ................................................................................. 7
`Table 6: Test for Dose-Tumor Positive Linear Trend in Tumors for Male Rats, Excluding Saline ............. 10
`Table 7: Test for Dose-Tumor Positive Linear Trend in Tumors for Female Rats, Excluding Saline .......... 12
`Table 8: Test for Dose—Tumor Positive Linear Trend in Tumors for Male Rats, Excluding Saline and High
`Dose ..................................................................................................................................................... 14
`
`TABLE OF FIGURES
`
`Figure l: Kaplan-Meier Estimates of Survival Curves in Male Rats, Controls Only ...............
`
`Figure 2: Kaplan-Meier Estimates of Survival Curves in Female Rats, Controls Only....
`
`Figure 3: Kaplan-Meier Estimates of Survival Curves in Male Rats, Excluding Saline ..............
`Figure 4: Kaplan-Meier Estimates of Survival Curves in Female Rats, Excluding Saline ............................. 8
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`

`1
`
`BACKGROUND
`
`Reference is made to the statistical consult request dated November 28, 2001, by Dr. Rosario, the
`reviewing pharmacologist, for a statistical review of the carcinogenicity study in the NDA
`submission.
`
`The carcinogenicity data were first submitted on October 29, 2001. Since certain variables were
`not coded properly, a request was made by the Division on December 6 to ask the sponsor to re-
`examine and to re-submit the data. The updated data were submitted on December 1 l, 2001.
`
`This review is focused on dose—mortality and dose-tumor trends. Several comparisons are made
`for each sex: (1) the two vehicle controls and the saline group, (2) the two vehicle controls and
`the three lCI 182,780 groups, and (3) a pooled comparison of combined vehicles and combined
`treated.
`In addition, in male rats, the comparison among the two vehicle controls and the low and
`middle dose levels of ICI 182,780 groups are also made.
`
`2
`
`INTRODUCTION
`
`A carcinogenicity study was conducted in rats to assess the carcinogenic potential of ICI 182,780
`given intramuscularly at 15 or 30 day intervals. The study was designed as a 2-year study. Rats
`were randomly divided into 6 groups stratifying by sex. There were three controls and three
`separate dose level groups. The study design is listed in Table 1. It is noted, that the dosing
`schedule does not readily translate into an intuitive dose response, such as l, 2, 3. The low dose is
`given per kg of the animal but the medium and high doses are not adjusted by weight. As the
`animals grow, the low dose becomes much closer to the mid-dose when the 'per kg‘ dose is
`calculated. Therefore, this reviewer performed two analyses: one using 0, l, 2, 3 as weights in
`the dose-tumor trend tests and a pair-wise comparison of all controls with all treated, since final
`doses do not differ greatly from each other. No p-values are reported when the tumor findings
`depended on observing a gross lesion first in an area where tissues were not routinely collected
`(e.g. tail).
`
`In the study, all analyses were performed separately by sex. After the treatment period, all
`surviving animals were sacrificed. All animals were fully necropsied and histopathologically
`examined.
`
`Table 1: Study Design
`
`Dose Levels
`
`Dose Volume
`
`
`
`Group No.
`“mm"
`
`Number of animals
`
`
`m—
`
`
`
`o-zmum _so
`0.2m
`
`
`
`
`
`
`Dose limited to maximum injection volume of 0.2mL/rat.
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`
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`

`3
`
`SUMMARY OF SPONSOR’S ANALYSIS
`
`An apparent reduction was seen in the mortality rate for animals receiving ICl 182,780. This
`reduction was observed in both sexes and attained statistical significance (p<0.05) for all treated
`groups compared to their respective controls.
`
`An increase in the incidence of ovarian benign granulosa cell tumors was only recorded in the
`high dose female animals. There was also evidence of an increase in the incidence of testicular
`interstitial Leydig cell tumors in male animals given ICI 182,780. Interstitial cell adenomas were
`absent in the vehicle control groups and present at a low incidence in the saline control group.
`The sponsor noted, that the incidence in the high dose group was similar to controls whilst in the
`two low dose groups the incidence was slightly increased although within the expected range for
`this age and strain ofrat.
`
`It was concluded by the sponsor that ICI 182,780 showed no evidence for direct carcinogenic
`activity. Induction of benign ovarian granulosa cell tumors and benign testicular Leydig cell
`tumors was consistent with the pharmacological activity of an anti-estrogen.
`
`4 REVIEWER’S ANALYSIS AND CONCLUSIONS
`
`P-values for dose-mortality pair-wise or trend analyses are two-sided and are compared with a
`significance level of 0.05. P-values from analyses of dose-tumor positive linear trend are one-
`sided and are compared with a significance level of 0.05 for rare tumors, defined as tumors in the
`control group with a spontaneous tumor rate of 1% or less, and with a significance level of 0.01
`for common tumors. Exact permutation trend tests are used unless both incidental and fatal tumor
`types are found in the same time interval, in which case a normal approximation is used, which
`gives the 'asymptotic' p-value. For pair-wise comparisons, the levels of significance are 0.05 and
`0.0] for rare and common tumors, respectively.
`
`4.1
`
`REVIEWER’S ANALYSIS
`
`4.1.1 Comparisons among the Three Controls
`
`The number of rats in each group who died in different time intervals appears in Table 2. The
`Kaplan-Meier estimates of the survival curves appear in Figure l and Figure 2. The table and
`figures did not suggest a difference in survival curves in male rats. However, in female rats there
`is a suggestion of decreased survival in saline control.
`
`As there is no inherent order among the two vehicle and the saline groups, the tests for
`homogeneity are appropriate. Table 3 shows that there was no statistically significant
`heterogeneity (p>0.245) among the survival patterns of the three groups for either sex. The
`apparent decreased survival in the female saline group seen in the Kaplan Meier curves was not
`borne out numerically. Results of pair-wise comparisons also show no statistically significant
`difference in survival in either sex.
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`Results of the pair-wise comparisons among the three controls in male rats show no significant
`difference in tumor incidences at any tumor site.
`
`Results of the pair-wise comparisons among the three controls in female rats show no significant
`difference in tumor incidences at any tumor site, except for adenoma (pars distalis) of the
`pituitary. There were 37 incidences in the vehicle control 1 and 46 incidences in the saline group.
`Both exact and asymptotic p-values of the corresponding pair-wise comparison are identical and
`equal to 0.0124. This finding is nearly statistically significant at the significance level of 0.01
`when the tumor is considered common and when no further multiplicity adjustment for p-values
`is required.
`
`Table 2: Number of Deaths Per Control Group in Different Time Intervals.
`
`Vehicle Control 1
`
`Group
`Vehicle Control 2
`
`Saline Control
`
`Total
`
`0 — 52
`
`53 — 78
`
`79 — 91
`
`92 — 103
`
`104 — 104
`
`Total
`
`0 — 52
`
`53 — 78
`
`79 — 91
`
`92 — 103
`
`104 — 104
`
`APPEARS mis wA
`UN ORIGINAL Y
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`

`Table 3: Dose-Mortality Trend Tests‘ for Control Groups
`
`Time-Adjusted
`Trend Test
`
`Statistic
`
`P-value
`
`Dose-Mortality Trend
`Depart from Trend
`Homogeneity
`
`Dose-Mortality Trend
`Depart from Trend
`Homogeneity
`
`Dose-Mortality Trend
`Depart from Trend
`Homogeneity
`
`Dose—Mortality Trend
`Depart
`from Trend
`Homogeneity
`
`0.4724
`0.7817
`0.7434
`
`0.3992
`0.7667
`0.6707
`
`0.1514
`0.8778
`0.3532
`
`0.0965
`0.8236
`
`0.2451
`
`Kruskal-Wallis
`
`Kruskal-Wallis
`
`'fikmmfimnmmgfimmmflHmmgdeAmstdemMmmmdUkTfikDmaannllm
`Donald G. Thomas, National Cancer Institute.
`
`Figure l: Kaplan-Meier Estimates of Survival Curves in Male Rats’, Controls Only
`Kuhn—Muir fluvial “auction
`mm: RI
`
`
`
`2 ii E
`
`Due to limitation ofthe labeling, the saline control group is labeled as ‘2’ in the plot.
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`

`Figure 2: Kaplan-Meier Estimates of Survival Curves in Female Ratd, Controls Only
`Kuhn—Man Suviul “auction
`
`Wed 9—0—0 my.“
`
`O-O-D (:7ng
`
`v—‘——~'r
`
`2 l1 5
`
`Due to limitation of the labeling, the saline control group is labeled as ‘2’ in the plot.
`
`
`
`4.1.2 Comparisons among Vehicle Controls and Treated, Excluding Saline Control
`
`In this section the saline control group is excluded from the analysis because saline only served as
`a comparator to potential vehicle effects.
`In addition, results are reported from the analyses with
`both vehicle control groups combined.
`
`The number of rats in each group who died in different time intervals appears in Table 4. The
`Kaplan-Meier estimates of the survival curves appear in Figure 3 and Figure 4. The table and
`figures suggest an increased trend with treatment in survival in either sex. However, in male rats
`the increased survival trend seems to be greatly influenced by the high-dose group, whereas in
`female rats the control groups overlap and the treated groups overlap separately.
`
`The p-values from the dose-mortality trend tests appear in Table 5. The results of these tests
`confirm what is visually apparent form the Kaplan-Meier curves and the number of deaths per
`time interval. The p-value for the dose-mortality trend test is significant (p-value < 0.001) in
`either sex.
`
`The entire table of comparisons of organ specific tumors appears in Appendix 5.1. In male rats,
`there are no sites with a significant dose-tumor positive linear trend. All eleven testicular
`interstitial Leydig cell tumors appear in the treated groups, but in a non—linear pattern. Therefore,
`the p-value for the linear trend is not significant (exact p-value = 0.3148). However, results of
`the pooled comparison between the combined vehicle controls and the combined treated groups
`show a significant difference (exact p-value = 0.0068). In addition, the trend for lipoma of the
`subcutaneous tissue in male rats approaches statistical significance (exact p-value = 0.0514, non-
`overlapping time intervals for fatal and incidental tumors) at a significance level of 0.05.
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`

`In female rats, a positive linear trend for ovarian granulosa cell tumors is found statistically
`significant (exact p-value = 0.0001) at a significance level of 0.05. Results of the pooled
`comparison between the combined vehicle controls and the combined treated groups also show a
`significant difference (exact p-value = 0.0126). In addition, the trend for fibrosarcoma of the
`subcutaneous tissue in female rats is statistically significant (exact p-value = 0.0366, non-
`overlapping time intervals for fatal and incidental tumors) at a significance level of 0.05.
`
`Table 4: Number of Deaths Per Treatment Group in Different Time Intervals, Excluding
`Saline
`
`Vehicle
`Control 1
`
`Vehicle
`Control 2
`
`0 — 52
`
`53—78
`
`79—91
`
`92—103
`
`lO4—l04
`
`Total
`
`Total
`
`0—52
`
`53—78
`
`79—91
`
`92~l03
`
`104—104
`
`APPEARS THIS WAY
`on ORIGINAL
`
`f-
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`

`Table 5: Dose-Mortality Trend Tests’, Excluding Saline
`
`Method
`
`Time-Adjusted
`Trend Test
`
`Statistic
`
`Dose-Mortality Trend
`Depart from Trend
`Homogeneity
`
`
`
`Kruskal-Wallis Dose-Mortality Trend
`Depart from Trend
`Homogeneity
`
`Dose-Mortality Trend
`Depart
`from Trend
`Homogeneity
`
`Kruskal-Wallis Dose—Mortality Trend
`Depart
`from Trend
`Homogeneity
`
`0.0000
`0.3542
`0.0003
`
`0.0000
`0.3625
`0.0001
`
`0.0001
`0.0262
`0 0001
`
`0.0002
`0.0282
`0.0001
`
`This test is run using Trend and Homogeneity Analyses ofProportions and Life Table Data Version 2.] by
`Donald G. Thomas, National Cancer lnstitute.
`
`Figure 3: Kaplan-Meier Estimates of Survival Curves in Male Rats, Excluding Saline
`Kaila—Man Swirl] Mancini:
`
`Peru-I
`
`"Viv-l
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`
`

`

`Figure 4: Kaplan-Meier Estimates of Survival Curves in Female Rats, Excluding Saline
`
`Karin—Muir Suvvd Mu
`
`
`
`4.1.3 Comparisons among Vehicle Controls and Treated, Excluding Saline Control
`and High Dose Level, Male Rats Only
`
`In the previous section, though there were eleven testicular interstitial Leydig cell tumors and all
`among the treated, the linear trend test did not reach statistical significance. In order to explore
`this finding, the dose-tumor trend analysis in male rats is repeated in this section but with the high
`dose level removed.
`
`The entire table of comparisons of organ specific tumors appears in Appendix 5.2. The p-value
`for the testicular interstitial Leydi g cell tumors now reaches statistical significance when the high
`dose level is removed from the analysis (p-value = 0.0206 as compared to 0.3148 when included).
`This reviewer is aware that the decision to exclude the high dose fi'om the analysis was post—hoe
`and is therefore, biased. However, as mentioned above, attributing a right order to the doses of
`ICI 182,780 administered to the rats is not straightforward in this study and the non-linear trend
`observed among the testicular interstitial Leydig cell tumors may reflect this problem. Also, the
`trend in lipoma in the subcutaneous tissue is no longer statistically significant at a significance
`level of 0.05 (p-value = 0.0682).
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`
`WNWNON0 NMSlHlSHVElddV
`
`

`

`4.2
`
`REVIEWER’S CONCLUSIONS
`
`4.2.] Conclusions for Comparisons among the Three Controls
`
`In male rats, results of the pair-wise comparisons among the three controls show no significant
`difference in tumor incidences at any tumor site.
`
`In female rats, 37 incidences of adenoma (pars distali) of the pituitary appear in the vehicle
`control 1 and 46 in the saline control. The pair-wise comparison approaches statistical
`significance (p-value = 0.0124) when the tumor is considered common and when no further
`multiplicity adjustment for p-values is required.
`
`4.2.2 Conclusions for Comparisons among the Two Vehicle Controls and the Treated
`
`In male rats, there is a statistically significant relationship between dose and increased length of
`survival (p-value < 0.001). There is also a statistically significant dose-tumor positive linear
`trend for the testicular interstitial Leydig cell tumors (p-value = 0.0206) when the high dose level
`is excluded from the comparison. The finding is not significant (p-value = 0.3148) when the high
`dose level is included into the analysis. However, results of the pooled comparison of this tumor
`between the combined vehicle controls and the combined treated groups show a significant
`difference (exact p-value = 0.0068).
`In addition, the trend for lipoma of the subcutaneous tissue
`approaches statistical significance (exact p-value = 0.0514) at a significance level of 0.05.
`
`In female rats, there is a statistically significant relationship between dose and increased length of
`survival (p-value < 0.001). There is also a statistically significant dose-tumor positive linear
`trend for the ovarian granulosa cell tumors (p-value = 0.0001) where 7 of the 10 incidences
`occurred in the high-dose group. Results of the pooled comparison in this tumor site between the
`combined vehicle controls and the combined treated groups also show a significant difference
`(exact p-value = 0.0126).
`In addition, the trend for fibrosarcoma of the subcutaneous tissue is
`statistically significant (exact p-value = 0.0366) at a significance level of 0.05.
`
`4.2.3 Overall Conclusions
`
`A nearly significant difference in tumor incidences is found in adenoma (pars distalis) of the
`pituitary in female rats between the vehicle control 1 and the saline control when the tumor is
`considered common and when no further multiplicity adjustment for p-values is required.
`
`The statistical findings in this review are similar to the sponsor’s report with respect to analyses
`of dose-mortality trend, of dose-tumor positive linear trend for the testicular interstitial Leydig
`cell tumors and for ovarian granulosa cell tumors. However, due to the difficulty in assigning
`proper dose levels reflecting the changing relationship of the doses administered, this reviewer
`considers the comparison of the combined vehicle controls and the combined treated as the most
`appropriate.
`In these analyses, the differences in testicular interstitial Leydig cell tumors and in
`ovarian granulosa cell tumors reach statistical significance. Other factors associated with these
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`9
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`

`

`findings (such as attributing the findings to the pharmacological activity of an anti-estrogen) are
`beyond this review.
`
`5 APPENDIX
`
`5.1
`
`TUMOR FINDINGS FOR VEHICLE AND TREATED GROUPS, EXCLUDING SALINE
`
`CONTROL
`
`Table 6: Test for Dose-Tumor Positive Linear Trend in Tumors for Male Rats, Excluding
`Safine
`
`xac! As m
`
`-e
`
`BRAIN
`
`BRAIN
`
`HEART
`HEART
`LIVER
`LIVER
`LIVER
`PANCREAS
`PANCREAS
`PANCREAS
`KIDNEY
`KIDNEY
`URINARY
`BLADDER
`URINARY
`BLADDER
`TESTIS
`SEMINAL VESICLE
`Sngglé'l-ANEOUS
`SUBCUTANEOUS
`TISSUE
`SUBCUTANEOUS
`ISSUE
`SUBCUTANEOUS
`ISSUE
`SUBCUTANEOUS
`ISSUE
`SUBCUTANEOUS
`ISSUE
`SUBCUTANEOUS
`TISSUE
`PITUITARY
`ITUITARY
`HYROID
`YROID
`
`
`
`
`
`”1000019466
`“-3378 0.2237
`”.7568 08286
`_I_0000 0.9237
`”1.0000 0.9228
`I. 1 '0000
`0.9478
`Mal1gnant schwannoma:
`[-_0.7871 07916
`arcinoma: heatocellular
`0.3 350
`0.3334
`Adenoma: heatocellular
`“0.5270 0.5410
`holanioma
`_-0.7579 0.7613
`denoma: islet cell
`__O.3378 0.2287
`-denoma: acinar cell
`arcinoma: islet cell _ 0.7264
`.7305
`i.oma
`_[_1.4000 0.3973
`denoma: tubular ch1
`“0.5270 0.5410
`“1.0000 0.9637
`1.0000
`0.9228
`0.3148
`0.3150
`I .0000
`.9228
`0 .5589
`105141.0360
`
`Mali~nant_-nularccllt
`
`I.
`denoma: interstitial cel _
`-
`_
`Fibroma
`.
`
`>=w1:>15>r>-g§§§g{3.333333a0:3mo'éoan:a'=a“5%9’.Boat:ma(/1=1:ggEg2-o5’—ta:3ii3oP?
`
`. steosarcoma
`
`.
`
`I
`I
`I
`I
`denoma: oars distalis m
`Adenoma: narsintennedia _
`Adenoma: C—cell _
`
`.
`
`0
`
`
`iiiI“fiifififiifififiifiifiifiififlifii
`uN-N
`
`
`N
`
`X
`
`A
`
`X
`
`
`
`
`
`
`1.4615
`
`
`
`O kl! 00 U).
`
`7
`
`.1667
`
`.
`
`4
`
`
`
`7
`
`O i5 oo
`02963
`0.2832
`1.0000
`0.8906
`1.0000
`0.9160
`0996719965
`0.1223
`.1039
`0.7508
`0.7536
`[-5603 0.5613
`
`
`
`NDA 21344 (Faslodex) Carcinogenicity Review
`
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`
`

`

`0.1740
`
`
`
`047244
`0.4482
`
`.9789
`.6850
`.9711
`.1689
`I 9483
`
`L9088
`
`
`
`N
`m
`
`><
`
`iiiiifiifififififiiiifiififiifili
`
`
`
`
`
`
`
`_ 0.1967
`I
`
`_ 0.6975
`7
`I4476
`
`_ .0000
`_ .69l7
`_ .0000
`_ .1692
`.0000
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HYROID
`PARATHYROID
`
`
`
`Adenomazfollicularcell
`
`
`
`Inheochromoc om
`
`ADRENAL
`JRENAL
`
`Bemg“
`pheochromoc oma
`HEMOLYM. TISSUE Mali_nantl
`homa
`HEMOLYM.TISSUE-_
`MAMMARY GLAND Adenocarcinoma
`MAMMARY GLAND denoma
`MAMMARY GLAND ibroma
`-Keratoacanthoma
`MISCELLANEOUS
`SKIN
`.
`_F1broma: dermal
`
`MISCELLANEOUS
`
`yp
`
`MISCELLANEOUS
`_Fibrosarcoma
`MISCELLANEOUS
`_Adenoma‘ sebaceous
`MISCELLANEOUS
`'
`-Pa illoma' s uamous cell
`MISCELLANEOUS
`p
`' q
`C-rcinoma' squamous cell
`MISCELLANEOUS
`‘
`—_Hibernoma:benin
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`_.o_..—oO.__—-._.\>
`
`
`
`I.6823
`
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`
`I.0000
`
`I.9l63
`
`.7429
`
`I.9366
`
`.0000
`.0000
`
`-7|33
`.0000
`
`
`
`NDA 21344 (Faslodex) Carcinogenicity Review
`
`1 1
`
`

`

`Table 7: Test for Dose-Tumor Positive Linear Trend in Tumors for Female Rats, Excluding
`Saline
`
`
`
`
`m:
`”1“?“
`WWW 0.9285
`MENINGES __l-_l-E-E-E--
`CAVITY ORAL ___E_Ll-__-
`_-_-.89|-__l-_090
`LIVER
`0—---.715I 0.7197
`1—0000
`_denomazisletcell mow”
`—Carcinoma: Islet cell ---l-_I-_-
`l-Lioma
`___-:-_-_
`KIDNEY
`'denomazrubularcell mnmooo 0.9597
`KIDNEY
`arcinoma:mbularcell _____0.03 0.7272
`SUBCUTANEOUS
`.
`
`
`
`
`.—
`.”
`
`HUI-I
`uu------
`
`SUBCUTANEOUS
`
`SUBCUTANEOUS
`
`0—-.90l9
`—--____--
`{_—--_-__I-mml
`UTERUS
`Pol :endometrial stroma _____-0.9996
`ursnus
`l-—_.0000
`UTERUS mmmo .9340
`
`PITUITARY —----I.oooo
`PITUITARY 0—_-.9669
`PITUITARY mafia
`HYROID
`AdenomarC-cell
`_I---I-0.2240
`THYROID 0_|-l---l-.5840 0.5924
`HYROID
`Carcinoma: follicularcel __I___—f--
`HYROID
`denomazfollicularcell _--_—-_l-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`wow
`—_-___'.9888
`Am “II-I'm
`ADRENAL —-_i-l-I-l.6677
`HEMOLYM. TISSUE m-l---_-_E_l-
`HEMOLYM. TISSUE 0-1—-_I-_8312
`HEMOLYMTISSUE mum-02000 0.1325
`i_—__—-_l-E-__
`MAMMARY GLAND __--fl-ll-_l-_
`MAMMARY GLAND1—0000
`MAMMARY GLAND _lls---{I-_l---
`——-.9962
`5er
`MISCELLANEOUS —-..' --9490
`SKIN
`Fibroma
`0
`04639
`04688
`MISCELLANEOUS
`'
`‘
`
`
`
`
`
`
`
`—____—___—__—_____
`
`heochromoc oma
`
`IN
`
`NDA 21344 (Faslodex) Carcinogenicity Review
`
`12
`
`

`

`
`
`
`SKIN
`MISCELLANEOUS
`SKIN
`MISCELLANEOUS
`
`Pa ilIoma' s uamous cell
`P
`' q
`.
`.
`Carcmoma. squamous cell
`
`MISCELLANEOUS
`‘
`DIAPHRAGM
`O steosarcoma metastasis EIIIII
`SCLE SKELETAL
`.
`Hemangnoma__I
`CIIIII
`EINHIIIIIIIIIIIIIIIIIllflfliiiflillllllllllll
`211'”:
`ibrosarcoma
`CIIIII
`IIIIII
`EEIIRIQIIIIIIIIIIIIlflifliiflilflifliilllllll
`'n
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`EIHEEHIEEIIIIIIIIIliflfliiiiflflflillllllllll
`:I'.‘
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`
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`
`0.4688
`
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`
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`EIIIIIIIEIIIIIIIIIIIIII
`E
`.2366
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`'11
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`—
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`
`APPEARS THIS WAY
`0“ ORIGINAL
`
`NDA 21344 (Faslodex) Carcinogenicity Review
`
`l3
`
`

`

`5.2
`
`TUMOR FINDINGS FOR VEHICLE AND TREATED GROUPS, EXCLUDING SALINE
`
`CONTROL AND HIGH DOSE LEVEL, MALE RATS ONLY
`
`Table 8: Test for Dose—Tumor Positive Linear Trend in Tumors for Male Rats, Excluding
`Saline and High Dose
`
`CI” "2'“ LowMM
`Malinantanularcellt MLOOOO 0.9428
`BRAIN
`-_t-i-Il-l_.6327 0.6986
`BRAIN
`I—.0000 0.9353
`HEART
`_M-E-IDOOO 0.9192
`_Mali an: schwannoma: endMIMI) 0.9436
`LIVER
`Carcinoma: heatoccllular _--_0.5795 0.5906
`IVER
`Adenoma: he-atocellular _O-_-4365
`LIVER
`Cholan ioma M02857 I .2347
`PANCREAS
`Adenoma: islet cell
`_m0.8987 I.8967
`PANCREAs
`Carcinoma: islet cell __--0. I4 I 8
`I . I 394
`KIDNEY
`Li oma
`____0.2395 0.2303
`KIDNEY
`Adenoma: tubular cell M02857
`RINARY
`.
`
`
`
`SUBCUTANEOUS
`
`
`
`
`
`
`
`.
`,
`.,
`URINARY
`0.9192
`Paleloma. transmonal c III. [.0000
`BLADDER
`Adenoma: interstitial cel M00206 {EH-—
`ESTlS
`SEMINAL VESICLE -—E-l-E-_I.oooo 0.9I92
`--u-
`.
`
`
`
`
`
`
`
`
`
`
`SEBSSJIIJETANEOUS
`
`Rhabdomyosarcoma In“. I .0909
`
`0.0554
`
`SfiggléTANEOUS
`
`Squamous cell carcinoma: “-“10000 0.9245
`
`0.9834
`Adenoma: ars distalis m 0.9843
`PITUITARY
`PITUITARY __I__l_l-2895 I.2303
`YROID
`Adenoma: C-cell
`l-_-- I .6272
`I .634 I
`HYROID _l-_--I.5192 .5254
`HYROID
`Adenoma: follicular cell ____ .2857
`0.2347
`
`
`
`
`
`
`
`
`Mali-unanthcochromoc o ___-0.7l43 I.7227
`ADRENAL
`- DRENAL o—l-.5030 .5113
`- DRENAL “mo-.0775 I.0760
`HEMOLYM.TISSUE Mali_ antl
`homa Wmooo I.9453
`HEMOLYM- TISSUEmom I.9738
`MAMMARY GLAND __EI-__ I .0000
`I.9600
`MAMMARY GLAND—L-i-l-_I.4359 0.5393
`MAMMARY GLAND__l-__ I .0000
`IBM?
`SKIN
`
`
`
`
`
`
`
`
`
`
`
`NDA 21344 (Faslodex) Carcinogenicity Review
`
`14
`
`

`

`I.EOa Q. (17aa
`
`SKIN
`MISCELLANEOUS
`SKIN
`MISCELLANEOUS
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`SKIN
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`__-______
`ABDOMEN
`Leiom osarcoma _____-
`0——M5941 06838
`
`—-—_m1-0000
`
`APPEARS THIS WAY
`on ORIGINAL
`
`
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`NDA 21344 (Faslodex) Carcinogenicity Review
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`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Peiling Yang
`12/20/01 11:42:22 AM
`BIOMETRICS
`
`Roswitha Kelly
`12/20/01 12:05:12 PM
`BIOMETRICS
`
`George Chi
`12/21/01 11:32:21 AM
`BIOMETRICS
`
`

`

`Executive CAC
`
`Date of Meeting; December 4, 2001
`Rat Carcinogenicity Study
`
`Committee:
`
`Joseph DeGeorge, Ph.D., HFD-024, Chair
`Joseph Contrera, Ph.D., HFD-901, Member
`Timothy McGovern, Ph.D., HFD—l 70, Alternate Member
`David Morse, Ph.D. Supervisory Pharmacologist, HFD-ISO
`Lilliam Rosario, Ph.D., Pharm-Tox Reviewer, HFD-l 50
`
`Author of Draft: Lilliam Rosario, PhD.
`
`The following information reflects a brief summary of the Committee discussion and its
`recommendations. Detailed study information can be found in the individual review.
`
`NDA # 21,344
`
`Drug Name: Faslodex (Fulvestrant; ICI 182,780
`Sponsor: Astra Zeneca Pharmaceuticals
`
`Mouse Carcinogenicity Study: Not conducted
`
`Background
`This 2-year carcinogenicity study in rats was submitted to NDA 21,344. This NDA proposes the
`use of ICI 182,780 (fulvestrant) for the treatment 01 -
`g
`——
`-—
`DWFT
`~
`
`,
`
`The recommended dose of Faslodex is 250 mg to be administered intramuscularly (IM)
`
`monthly.
`
`The Sponsor indicates fulvestrant is an antiestrogenic agent, which acts by downregulation of the
`estrogen receptor (ER). Fulvestrant binds ER in a competitive manner with a high affinity
`comparable to estradiol. Further, the Sponsor suggests that Fulvestrant is a non-agonist
`antiestrogen which blocks the uterotrophic action of estradiol in mice, rats and monkeys without
`itself having any partial agonist estrogen— like activity.
`
`Genotoxicity
`The mutagenic and clastogenic potential of ICI 182,780 has been studied in bacterial mutation
`assays in strains of Salmonella typhimurium and Escherischia coli, an in vitro cytogenetics assay
`in cultured human lymphocytes, 3 mouse lymphoma mutation assay, and an in vivo rat
`micronucleus test. ICI 182,780 has shown no evidence of genotoxic/clastogenic potential in this
`battery of tests.
`
`

`

`Rat Carcinogenicig Study:
`
`Study Design:
`
`Dose concurrence was obtained on July 28, 1998.
`
`The Sponsor selected the high dose level to represent the maximum possible dose by the IM
`route (maximum feasible dose).
`
`There were 6 groups (50 sex/group); Sprague Dawley rats . ”IL——
`Control-l (Cl):
`Vehicle/15 days
`Control-2 (C2):
`Vehicle/3O days
`Control-3 (C3):
`Saline/15 days
`Low Dose (LD):
`15 mg/kg/3O days
`Middle Dose (MD):
`10 mg/rat/30 days
`High Dose- (HD);
`10 mg/rat/ 15 days
`
`The following table shows the ~ actual dose (mg/kg) administered to Groups V (10
`mg/rat/30days) and Group VI (10 mg/rat/l 5 days). For comparison purposes, these values have
`also been normalized for frequency of administration (from every 15 days to every 30 days)
`
`
`Group V
`10 m_/rat/30 da 5
`
`Group V1
`10 m/rat/lS da s
`
`
`
`
`
`
`
`
`Sex Week Body
`weight
`
`mg/kg/
`30 days
`
`Male
`
`I.
`E‘-
`
`
`
`2578
`-
`-
`
`
`
`.
`
`mg/kg/ mg/kg/30
`15 days
`days
`
`
`
`
`
`
`
`
`
`
`
`C
`
`m
`
`Statistical Methods:
`
`All tests for tumor incidence were one—sided looking for an increase in response/incidence.
`
`The Haseman (1983) principle of statistical significance was adopted; a rare tumor (<1%
`spontaneous incidence) will be deemed statistically significant if p<0.05, and a common
`tumor shall be deemed significant if p<0.01.
`
`The statistical comparisons of interest were implemented using Peto’s survival-adjusted trend
`test.
`
`Note that the significance values used by the Sponsor are in accordance with those employed
`by CDER when only a single carcinogenicity study is conducted. The probability levels for
`determining significance of tumor incidence has not been adjusted for multiple statistical
`comparisons as would be appropriate to maintain a constant error rate over multiple studies.
`
`

`

`RAT TUMOR FINDINGS:
`
`It appears that the IM administration of ICI 182,780 (fulvestrant) for 24 months increased the
`incidence of ovarian granulosa cell tumors and testicular Leydig cell tumors in female and male
`rats, respectively.
`
`Ovaries:
`
`A 14% increase in the incidence of a rare ovarian granulosa cell tumors in the high dose
`female animals (7/50 rats at 10 mg/rat/l 5d; p=0.01887).
`
`Spontaneous incidence of granulosa cell tumors for this strain of rat is 0.06% (n=1729)
`(Giknis and Clifford, 2001 ‘P—-""-"""—'“
`
`The conducting laboratory reports background instances varying from O/ 120 to 1/120 (0.2%).
`Another study (n=4493) with the same strain and source reports 0.3% (Gregson and Abbott,
`1984)
`
`Testes:
`
`There was increase incidence (2-12%) of interstitial Leydig cell tumors (adenomas-common)
`in drug-treated animals.
`
`These tumors were present at a low incidence (4%) in the saline control group and absent in
`the vehicle control groups. The incidence in the high dose group was similar to controls (2%)
`while slightly increased (8-12%) in the two low dose groups,
`In Group 4 (15 mg/kg/30 days), interstitial cell tumors were increased significantly
`(p=0.01922)
`
`Spontaneous incidence for this strain of rat is 2.35% 1 m
`
`The reviewer proposed 3 questions for the EXEC CAC committee:
`
`1. Are the survival rates observed in control and drug-treated groups adequate to determine the
`carcinogenic potential of ICI 182,780 (fulvestrant)?
`
`0 Even though survival rates appear lower than expected for control males, the Committee
`agreed that the rate of mortality is adequate to determine the carcinogenic potential of ICI
`182,780.
`
`Does the Committee agree that administration of ICI 182,780 increases the incidence of
`granulosa cell tumors and interstitial Leydig cell tumors?
`
`The Committee
`
`0
`
`0
`
`0
`
`0
`
`agreed that administration of ICI 182,780 increases the incidence of both granulosa cell
`tumors and interstitial Leydig cell tumors, in females and males, respectively.
`recommended the statistical evaluation of these results take into consideration that only
`one carcinogenicity study was submitted.
`
`recommended to carefully examine the pharmacological data submitted to support the
`claim that ICI 182,780 is a “non-agonist” antiestrogen. The increase incidence of
`interstitial Leydig cell tumors in males may suggest a drug-induced estrogenic effect.
`
`noted that while the carcinogenicity study was acceptable, the Sponsor did not perform
`the defining s